EP0882732A1 - Taxoid-Derivate und Verfahren zu deren Herstellung - Google Patents

Taxoid-Derivate und Verfahren zu deren Herstellung Download PDF

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Publication number
EP0882732A1
EP0882732A1 EP97109052A EP97109052A EP0882732A1 EP 0882732 A1 EP0882732 A1 EP 0882732A1 EP 97109052 A EP97109052 A EP 97109052A EP 97109052 A EP97109052 A EP 97109052A EP 0882732 A1 EP0882732 A1 EP 0882732A1
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EP
European Patent Office
Prior art keywords
paclitaxel
docetaxel
represented
following formula
glucosyloxyacetyl
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP97109052A
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English (en)
French (fr)
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EP0882732B1 (de
Inventor
Tadakatsu c/o Kurashiki Uni. of Sci. & Art Mandai
Hiroshi c/o Kurashiki Univ. of Sci. & Art Okumoto
Koji c/o Ensuiko Sugar Refining Co. Ltd Hara
Katsuhiko c/o Ensuiko Sugar Refi. Co. Ltd Mikuni
Kozo c/o Ensuiko Sugar Refining. Co. Ltd Hara
Hiroki c/o Okayamarika-Daigaku Hamada
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mandai Tadakatsu
Ensuiko Sugar Refining Co Ltd
Original Assignee
KAREN PHARMACEUTICAL CO Ltd
Mandai Tadakatsu
Kaken Pharmaceutical Co Ltd
Ensuiko Sugar Refining Co Ltd
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Filing date
Publication date
Priority to CA002206739A priority Critical patent/CA2206739C/en
Priority to HU9700991A priority patent/HU224589B1/hu
Application filed by KAREN PHARMACEUTICAL CO Ltd, Mandai Tadakatsu, Kaken Pharmaceutical Co Ltd, Ensuiko Sugar Refining Co Ltd filed Critical KAREN PHARMACEUTICAL CO Ltd
Priority to DE69727916T priority patent/DE69727916T2/de
Priority to EP97109052A priority patent/EP0882732B1/de
Publication of EP0882732A1 publication Critical patent/EP0882732A1/de
Application granted granted Critical
Publication of EP0882732B1 publication Critical patent/EP0882732B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

  • the present invention relates to a taxoid derivative and a method of producing it and, in detail, a taxoid derivative of which physiological activity and solubility in water were improved by combining a sugar with any one of paclitaxel, docetaxel and 10-deacetyl-baccatin III via a spacer, and a method of producing the said derivative.
  • Paclitaxel (trade name, Taxol)is a diterpene compound [M. C. Wani et al. : J. Am. Chem. Soc., 93, 2325 (1971)] isolated from the bark of Taxus brevifolia growing in North America and known as a powerful anticancer drug having an improved effect on uncurable cancer by a hitherto known chemical therapy.
  • the mechanism of controling cancer with paclitaxel is unique and, while other anticancer drugs control formation of the microtubule which the main component of the spindle, that is a mitosis device, paclitaxel causes excess formation of microtubules and thereby, controls mitosis.
  • paclitaxel is a powerful anticancer drug, its solubility in water is low, and its utility as a medical drug is limited. Because of this, use of a solubilizing agent and studies and developments, etc. to enhance its solubility by preparing derivatives are being actively carried out. However, no sufficient measures to solve this matter have yet been found. For example, paclitaxel is at present administered to a patient using a solubilizing agent "Cremophore", and 1 liter of the solution is administered over 6 hours every two weeks, a four-run of which is carried out, thus being a heavy burden on patients [Eric K. Rowinsky et al., CANCER RESEARCH 49, 4640 (1989)]. Moreover, side effects of the solubilizing agent have become a problem.
  • docetaxel (trade name: Taxotere) was developed as a paclitaxel derivative having improved solubility, the solubility of docetaxel in water is only 1.3 times that of paclitaxel [I. Ringer et al., J. Natl. Cancer Inst., 83, 288 (1991)], therefore it is not much improved.
  • paclitaxel derivative in which sugar is combined with paclitaxel by an ether linkage via a spacer, shows increased solubility in water and physiological activity.
  • the present invention relates to taxoid derivatives wherein sugar is combined with any one of paclitaxel, docetaxel and 10-deacetylbaccatin III via a spacer and to a method for producing the said derivatives.
  • Glucosyloxyacetyl-7-paclitaxel represented by the following formula (hereinafter, abbreviated to 7-S-paclitaxel),
  • Glucosyloxyacetyl-2'-paclitaxel represented by the following formula (hereinafter, abbreviated as 2'-S-paclitaxel),
  • Diglucosyloxyacetyl-2',7-paclitaxel represented by the following formula (hereinafter, abbreviated to 2',7-S-paclitaxel),
  • Glucosyloxyacetyl-10-paclitaxel represented by the following formula (hereinafter, abbreviated to 10-S-paclitaxel),
  • N-(glucosyloxyacetyl)-N-debenzoylpaclitaxel represented by the following formula (hereinafter, abbreviated to 3'-S-paclitaxel),
  • N-(glucosyloxyacetyl)-N-debutoxycarbonyldocetaxel represented by the following formula (hereinafter, abbreviated as 3'-S-docetaxel),
  • Glucosyloxyacetyl-2'-docetaxel represented by the following formula (hereinafter, abbreviated as 2'-S-docetaxel),
  • Diglucosyloxyacetyl-2',7-docetaxel represented by the following formula (hereinafter, abbreviated as 2',7-S-docetaxel),
  • Triglucosyloxyacetyl-2',7,10-docetaxel represented by the following formula (hereinafter, abbreviated as 2',7,10-S-docetaxel),
  • Glucosyloxyacetyl-7-docetaxel represented by the following formula (hereinafter, abbreviated as 7-S-docetaxel),
  • Diglucosyloxyacetyl-7,10-docetaxel represented by the following formula (hereinafter, abbreviated as 7,10-S-docetaxel),
  • Glucosyloxyacetyl-10-docetaxel represented by the following formula (hereinafter, abbreviated as 10-S-docetaxel),
  • Glucosyloxyacetyl-10-baccatin III represented by the following formula (hereinafter, abbreviated as 10-S-baccatin III),
  • a taxoid derivative of this invention is made by combining sugar with any one of paclitaxel, docetaxel and 10-deacetylbaccatin III via a spacer.
  • Paclitaxel is obtained by isolating it from the bark of Taxus brevifolia growing in North America according to a method described in Springfield, D. G. I. : Pharmacol. Ther., 52, 1 (1992) and, in addition, paclitaxel synthesized by chemical synthesis can also used (R. A. Holton: Europian Patent-A 400971, 1990). Also, docetaxel is derived from paclitaxel according to a method described in Greene. A. E. et al.: J. Org. Chem. 59, 1238 (1994). 10-Deacetyl-baccatin III is a natural product extracted from Taxus brevifolia growing in North America as aforementioned.
  • a reaction combining sugar with any one of paclitaxel, docetaxel and 10-deacetyl-baccatin III via a spacer is carried out by using tetrabenzyl acetyloxyglucoside.
  • This tetrabenzyl acetyloxyglucoside, an ester compound is prepared by combining a glycolate such as ethyl glycolate etc., that is a spacer, with tetrabenzylglucose obtained by using glucose as a starting substance according to an usual procedure, followed by deethylation of the ester yielding the tetrabenzyl acetyloxyglucoside as a carboxylic acid compound which is represented by the following formula.
  • An ethyl ester (compound (2), molecular weight 626.76) is obtained by the method that tetrabenzylglucose (1) obtained according to an usual procedure is treated with ethyl glycolate and p-toluenesulfonic acid in benzene at 0-150°C, preferably 110°C, for 0.5-50 hours, preferably 8 hours, so that the 1 position of tetrabenzylglucose (1) reacts with ethyl glycolate.
  • this reaction mixture is made to acidic by hydrochloric acid (for example, 1N-HCl) to cause a deethylation reaction, whereby a carboxylic acid compound is obtained which is tetrabenzyl acetyloxyglucoside (3).
  • hydrochloric acid for example, 1N-HCl
  • sugars which may be used are mannose, allose, altose, gulose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, psicose, fructose, sorbose, tagatose, fucose, maltose and so forth in addition to glucose.
  • a glycolate such as ethyl glycolate
  • the alkyl chain length of this substance can be easily adjusted.
  • a taxoid derivative of this invention can be produced by allowing any one of the aforementioned paclitaxel, docetaxel and 10-deacetylbaccatin III to react with tetrabenzyl acetyloxyglucoside.
  • methods for producing taxoid derivatives there are methods shown in the below-described reaction processes (I) and (II).
  • reaction process (I) is such that debenzylation is carried out after allowing paclitaxel (4) to react with tetrabenzyl acetyloxyglucoside (3) and, according to this method, 2'-S-paclitaxel (7) and 2',7-S-paclitaxel (8) are obtained.
  • paclitaxel (4) and tetrabenzyl acetyloxyglucoside (3) are allowed to react with a base such as 4-dimethylaminopyridine (DMAP) etc., a condensing reagent such as dicyclohexylcarbodiimide (DCC) etc. and a solvent such as methylene chloride etc. under an argon atmosphere at room temperature for 0.5-100 hours, preferably 16.5 hours, whereby the glucoside (5) of (6) is obtained.
  • a base such as 4-dimethylaminopyridine (DMAP) etc.
  • DCC dicyclohexylcarbodiimide
  • solvent such as methylene chloride etc.
  • the compound (5) or (6) is allowed to react with a catalyst such as palladium black etc. and an acid such as acetic acid etc. under a hydrogen atmosphere at room temperature with vigorous stirring for 0.5-50 hours, preferably 5 hours, whereby 2'-S-paclitaxel (7) and 2',7-S-paclitaxel (8) are obtained.
  • a catalyst such as palladium black etc.
  • an acid such as acetic acid etc.
  • the method (III) shown by the below-described reaction process is such that, after protecting the 2'-position of paclitaxel by using a chlorotriethylsilyl group, a reaction with tetrabenzyl acetyloxyglucoside followed by debenzylation and detriethylsilylation are carried out to produce a paclitaxel derivative.
  • paclitaxel (4) and a protecting reagent such as chlorotriethylsilane (TESCl) etc., a base such as imidazole etc. and a solvent such as dimethylformamide (DMF) etc. are allowed to react under an argon atmosphere at room temperature for 0.5-100 hours, preferably 19. 5 hours, whereby the 2' position of paclitaxel is protected by triethylsilane and the compound (16) is obtained.
  • a protecting reagent such as chlorotriethylsilane (TESCl) etc.
  • a base such as imidazole etc.
  • a solvent such as dimethylformamide (DMF) etc.
  • this obtained compound and tetrabenzyl acetyloxyglucoside (3), a base such as DMAP etc., a condensing reagent such as DCC etc. and a solvent such as methylene chloride etc. are allowed to react under an argon atmosphere at room temperature for 0.5-100 hours, preferably 5 hours, whereby the glycoside (17) is obtained.
  • the glycoside (17) and a catalyst such as palladium black etc. and an acid such as acetic acid etc. are allowed to react under a hydrogen atmosphere at room temperature with vigorous stirring for 0.5-50 hours, prefrably 5 hours, and to this reaction mixture a solvent such as tetrahydrofuran (THF) etc. and water are added to carry out a reaction at room temperature for 0.5-50 hours, prefrably 15 hours, whereby the aimed compound (18) is obtained which is 7-S-paclitaxel represented by the above formula.
  • a solvent such as tetrahydrofuran (THF) etc. and water
  • 10-deacetylpaclitaxel (22) instead of paclitaxel
  • 10-S-paclitaxel (23) represented by the below-described formula
  • N-debenzoylpaclitaxel (24) instead of paclitaxel
  • 3'-S-paclitaxel (25) represented by the below-described formula
  • 3'-S-docetaxel (38) can be obtained.
  • 10-deacetyl-baccatin III (26) instead of paclitaxel
  • 10-S-baccatin III (27) represented by the below-described formula can be obtained.
  • Taxoid derivatives of this invention can be separated easely into an anomer by applying liquid chromatography using a carrier having silica gel such as ODS etc. and thus, a purified sample is obtained which can be used as a medicine.
  • Taxoid derivatives all show increased solubility in water and, while the solubility of paclitaxel is 0.4 ⁇ g/ml, that of 7-S-paclitaxel is 14.7 ⁇ g/ml (36.8 times), 2'-S-paclitaxel 30.6 ⁇ g/ml (76.5 times) and 2',7-S-paclitaxel 48.4 ⁇ g/ml (121 times). These paclitaxel derivatives also show increased solubility in alcohol.
  • the present invention provides a taxoid derivative which shows a high solubility in water and improved physiological activity and a method for producing it. It is expected that the taxoid derivative reduces the burden patients and may be used as an effective drug for the treatment of cancer.
  • the compound (3) was dissolved into deuteriumchloroform and analyzed by 1 H-NMR, and each peak was assigned to determine its structure and thus, structure of the compound was confirmed as the above-described.
  • Debenzylation of 187 mg of the compound (5) was carried out by reacting with 50 mg of palladium black and 3 ml of acetic acid under a hydrogen atmosphere at room temperature with vigorous stirring for 5 hours, whereby 101 mg of 2'-S-paclitaxel (7) (C 55 H 63 NO 21 , molecular weight 1074.10) were obtained. The yield was 73 %.
  • debenzylation of 983 mg of the compound (6) was carried out by reacting with 200 mg of palladium black and 3 ml of acetic acid under a hydrogen atmosphere at room temperature with vigorous stirring for 5 hours, whereby 259 mg of 2',7-S-paclitaxel (8) (C 63 H 75 NO 28 , molecular weight 1294.28) were obtained. The yield was 41 %.
  • 7-S-paclitaxel was dissolved into deuteriumchloroform and analysed by 1 H-NMR and the structure was determined by assigning respective peaks. Results are shown below.
  • Paclitaxel, 7-S-paclitaxel, 2'-S-paclitaxel and 2',7-S-paclitaxel were separately dissolved into dimethylsulfoxide (DMSO), and an inclusion complex (made by Ensuiko Sugar Refining Co., Ltd.) of dimethyl- ⁇ -cyclodextrin (DM- ⁇ -CD, made by Ensuiko Sugar Refining Co., Ltd.) with paclitaxel was dissolved in water so that the concentrations of these compounds in the reaction solutions were adjusted at 5 ⁇ M.
  • DMSO dimethylsulfoxide
  • DM- ⁇ -CD dimethyl- ⁇ -cyclodextrin
  • each of the above-described samples is mixed with tubulin (a main constituting protein of the microtubule) and allowed to react at 37°C for 15 minutes. Absorbance at 350 nm of the reaction solution was measured at 2, 5, 10 and 15 minutes after initiation of the reaction. Also, after the reaction ended, calcium chloride was added and, 5 minutes after its addition, absorbance at 350 nm was again measured. From each measured value the relative activity of each sample was determined such that polymerization-promoting activity and depolymerization -inhibiting activity were taken as 100, and the results are shown in Table 2.
  • the depolymerization-inhibiting activity of 7-S-paclitaxel is more than twice as potent as that of paclitaxel and it was confirmed that 7-S-paclitaxel is a very effective anticancer drug. Also, it was recognized that the polymerization-promoting activity is enhanced by making a complex which includes paclitaxel in DM- ⁇ -CD.
  • Sample Polymerization-promoting activity Depolymerization-inhibiting activity
  • Example 2 Similar to Example 1, a mixture of 260 mg of docetaxel, 540 mg of tetrabenzyl acetyloxyglucoside obtained from Production Example 1, 110 mg of DMAP, 190 mg of DCC and 8 ml of methylene chloride was allowed to react under an argon atmosphere at room temperature for 16.5 hours, whereby the compound (10) having a glucoside at the 2' position, compound (11) having a glucoside at the 2',7 positions and compound (12) having a glucoside at the 2',7,10 positions were obtained.
  • docetaxel (9) instead of paclitaxel, in a similar manner to the above Example 2, the compound (28) in which the 2' position of docetaxel was protected by a triethylsilyl group (TES) was obtained and then, the compounds (29) and (30) were obtained by reacting the compound (28) with tetrabenzyl acetyloxyglucoside (3) obtained from Production Example 1. Then, benzyl groups and TES were removed from the compounds (29) and (30), whereby 7-S-docetaxel (19) and 7,10-S-docetaxel (20) were obtained. These are produced by the reaction process (IV).
  • TES triethylsilyl group
  • docetaxel (9) instead of paclitaxel, in a similar manner to the above Example 2, the compound (31) in which the 2',7 positions of docetaxel were protected by TES was obtained and then, the compound (32) was obtained by reacting the compound (31) with tetrabenzyl acetyloxyglucoside (3) obtained from Production Example 1. Then, benzyl groups and TES were removed from the compound (32), whereby 10-S-docetaxel (21) (C 51 H 65 NO 21 , molecular weight 1028.07)was obtained. This compound is produced by the reaction process (V).
  • N-debenzoylpaclitaxel (C 40 H 47 NO 13 ; molecular weight 749.81) (24) instead of paclitaxel, in a similar manner to the above Example 2, the compound (35) was obtained by reacting the compound with tetrabenzyl acetyloxyglucoside (3) obtained from Production Example 1. Then, benzyl groups were removed to obtain 3'-S-paclitaxel (C 48 H 59 NO 20 , molecular weight 969.99) (25). This compound is produced by the reaction process (VII).
  • N-debutoxycarbonyldocetaxel as a starting material, in a similar manner to the above-described, it is possible to produce N-(glucosyloxyacetyl)-N-debutoxycarbonyldocetaxel which is a docetaxel type glucoside of 3'-S-paclitaxel.

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EP97109052A 1997-06-03 1997-06-04 Taxoid-Derivate und Verfahren zu deren Herstellung Expired - Lifetime EP0882732B1 (de)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002206739A CA2206739C (en) 1997-06-03 1997-06-03 Taxoid derivative and method of producing thereof
HU9700991A HU224589B1 (hu) 1997-06-03 1997-06-03 Taxoidszármazékok és eljárás előállításukra
DE69727916T DE69727916T2 (de) 1997-06-04 1997-06-04 Taxoid-Derivate und Verfahren zu deren Herstellung
EP97109052A EP0882732B1 (de) 1997-06-03 1997-06-04 Taxoid-Derivate und Verfahren zu deren Herstellung

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CA002206739A CA2206739C (en) 1997-06-03 1997-06-03 Taxoid derivative and method of producing thereof
HU9700991A HU224589B1 (hu) 1997-06-03 1997-06-03 Taxoidszármazékok és eljárás előállításukra
EP97109052A EP0882732B1 (de) 1997-06-03 1997-06-04 Taxoid-Derivate und Verfahren zu deren Herstellung

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EP0882732A1 true EP0882732A1 (de) 1998-12-09
EP0882732B1 EP0882732B1 (de) 2004-03-03

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1022284A1 (de) * 1997-10-08 2000-07-26 Bio Research Corporation of Yokohama Taxoid-derivate und verfahren zu ihrer herstellung
WO2001056564A1 (en) * 2000-02-02 2001-08-09 Florida State University Research Foundation, Inc. C10 heterosubstituted acetate taxanes as antitumor agents
WO2001057029A1 (en) * 2000-02-02 2001-08-09 Florida State University Research Foundation, Inc. C7 heterosubstituted acetate taxanes as antitumor agents
WO2004063211A1 (en) * 2003-01-09 2004-07-29 Bioxel Pharma Inc. Carbohydrate derivatives of paclitaxel and docetaxel, method for producing same and use thereof
EP0882733B1 (de) * 1996-02-16 2005-09-14 Ensuiko Sugar Refining Company, Limited Acylierungsmittel und Verfahren zu deren Herstellung
US7524869B2 (en) 2000-02-02 2009-04-28 Florida State University Research Foundation, Inc. Taxanes having a C10 ester substituent
US8003812B2 (en) 2004-02-13 2011-08-23 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
US8242166B2 (en) 2008-03-31 2012-08-14 Florida State University Research Foundation, Inc. C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes
WO2013056662A1 (zh) * 2011-10-19 2013-04-25 上海贝美医药科技有限公司 新的紫杉烷类衍生物及其制备方法
CN110003291A (zh) * 2019-01-23 2019-07-12 天津科技大学 一种氟代糖基修饰的紫杉醇类化合物及其合成方法和应用

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0882733B1 (de) * 1996-02-16 2005-09-14 Ensuiko Sugar Refining Company, Limited Acylierungsmittel und Verfahren zu deren Herstellung
EP1022284A4 (de) * 1997-10-08 2002-01-30 Bio Res Corp Of Yokohama Taxoid-derivate und verfahren zu ihrer herstellung
EP1022284A1 (de) * 1997-10-08 2000-07-26 Bio Research Corporation of Yokohama Taxoid-derivate und verfahren zu ihrer herstellung
US6872837B2 (en) 2000-02-02 2005-03-29 Fsu Research Foundation, Inc. Taxanes having a c10 Heterosubstituted acetate substituent
US7157474B2 (en) 2000-02-02 2007-01-02 Fsu Research Foundation, Inc. C10 heterosubstituted acetate taxane compositions
US6673833B2 (en) 2000-02-02 2004-01-06 Fsu Research Foundation, Inc. C7 heterosubstituted acetate taxanes
US7524869B2 (en) 2000-02-02 2009-04-28 Florida State University Research Foundation, Inc. Taxanes having a C10 ester substituent
AU776765B2 (en) * 2000-02-02 2004-09-23 Florida State University Research Foundation, Inc. C7 heterosubstituted acetate taxanes as antitumor agents
AU776767B2 (en) * 2000-02-02 2004-09-23 Florida State University Research Foundation, Inc. C10 heterosubstituted acetate taxanes as antitumor agents
US6861446B2 (en) 2000-02-02 2005-03-01 Fsu Research Foundation, Inc. C7 heterosubstituted acetate taxane compositions
WO2001057029A1 (en) * 2000-02-02 2001-08-09 Florida State University Research Foundation, Inc. C7 heterosubstituted acetate taxanes as antitumor agents
WO2001056564A1 (en) * 2000-02-02 2001-08-09 Florida State University Research Foundation, Inc. C10 heterosubstituted acetate taxanes as antitumor agents
US6664275B2 (en) 2000-02-02 2003-12-16 Fsu Research Foundation, Inc. C10 heterosubstituted acetate taxanes
US7183312B2 (en) 2000-02-02 2007-02-27 Fsu Research Foundation, Inc. Taxanes having a C7 heterosubstituted acetate substituent
WO2004063211A1 (en) * 2003-01-09 2004-07-29 Bioxel Pharma Inc. Carbohydrate derivatives of paclitaxel and docetaxel, method for producing same and use thereof
US8003812B2 (en) 2004-02-13 2011-08-23 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
US8242166B2 (en) 2008-03-31 2012-08-14 Florida State University Research Foundation, Inc. C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes
WO2013056662A1 (zh) * 2011-10-19 2013-04-25 上海贝美医药科技有限公司 新的紫杉烷类衍生物及其制备方法
CN110003291A (zh) * 2019-01-23 2019-07-12 天津科技大学 一种氟代糖基修饰的紫杉醇类化合物及其合成方法和应用
CN110003291B (zh) * 2019-01-23 2022-11-29 天津科技大学 一种氟代糖基修饰的紫杉醇类化合物及其合成方法和应用

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HU224589B1 (hu) 2005-11-28
HUP9700991A3 (en) 1999-12-28
CA2206739C (en) 2006-10-10
CA2206739A1 (en) 1998-12-03
HUP9700991A2 (hu) 1998-12-28
HU9700991D0 (en) 1997-07-28
EP0882732B1 (de) 2004-03-03

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